- an inappropriate immune response that What makes an ...fpm/immunology/lectures/Chapter016.pdf · Hypersensitivity - an inappropriate immune response that causes damage to the individual

Hypersensitivity - an inappropriate immune response thatcauses damage to the individual

Type I hypersensitivity - mediated by IgE

Type II hypersensitivity - mediated by IgG

Type III hypersensitivity - mediated by immune complexes

Type IV hypersensitivity - cell-mediated

Immediate hypersensitivity - Types I, II and III

Delayed hypersensitivity - Type IV

What makes

an antigen to

be an

allergen?

Type I hypersensitivity = allergic

reactions

- Mast cells and basophils possess receptors

for the Fc region of IgE (FcεεεεRI). Eosinophilsbut ONLY after activation!!

- IgE produced in response to an antigen

(allergen) binds to mast cells and basophils.

- If antigen cross-links this IgE on the cell

surface, the FcεεεεRI are cross-linked– resulting

in degranulation of the cell and release of

vasoactive mediators (histamine,

leukotrienes, prostaglandins, cytokines etc).

Kuby Figure 16-2

I. PHASE 1

Kuby Figure 16-2

I. PHASE 2

1) The allergen enters the body and is recognized by sIg on a B-lymphocyte

2) The B-lymphocyte then proliferates and differentiates into plasma cells3) The plasma cells produce and secrete IgE which binds to receptors on

mast cells and basophils. 4) Allergen cross reacting with IgE on mast cell.

5) The next time the allergen enters the body, it cross-links the Fab portions

of the IgE bound to the mast cell. 6) This triggers the mast cell to degranulate and releases its histamine and

other inflammatory mediators. 7) The inflammatory mediators are now able to bind to receptors on target

cells which leads to dilation of blood vessels, constriction of bronchioles, excessive mucus secretion, and other symptoms of allergy.

RECAP:

1

2

0

Effector Mechanisms

• Immediate Allergic Reaction – caused by

mast cell degranulation

• Late-phase response – involves the

recruitment of Th2 cells, eosinophils, and

basophils

Figure 12-12 Figure 12-11

Localized allergic reactions - symptoms depend on the

location of mast cell/basophil degranulation

- Skin ---> eczema

- Nasal mucosa ---> allergic rhinitis (hay fever)

- Respiratory tract ---> asthma- Gastrointestinal tract ---> vomiting, diarrhea (food allergies)

Systemic allergic reaction = systemic anaphylaxis

- Systemic vasodilation results in an acute loss of blood pressure.- Bronchoconstriction causes asphyxiation.

- Death can occur within minutes.

Epinephrine counteracts the effects of allergic mediators on smooth

muscle and vasculature.

Figure 12-16 part 1 of 2-Due to histamine,

prostaglandins, and other

preformed mediators that

cause rapid increase in vasc.

Permeability and contraction

of smooth muscle

Late-Phase Reaction by

inducing synthesis and

release of mediators

including leukotrienes,

chemokines, and cytokines

from activated mast cells

Causes of allergic reactions (factors

predisposing to IgE responses):

Characteristics of the antigen- Certain antigens are more likely to induce IgE

responses (e.g. ragweed pollen)

Mode of presentation of the antigen- Dosage, adjuvant may influence the IgE vs IgG

response

Genetics of the individual- Certain mouse strains are more likely to make IgEresponses

- Parents with allergies are more likely to have children with allergies

Figure 16.10

Blame it on

your

parents!!!!

Kuby Figure 16-10

Figure 12-16 part 1 of 2-Due to histamine,

prostaglandins, and other

preformed mediators that

cause rapid increase in vasc.

Permeability and contraction

of smooth muscle

Late-Phase Reaction by

inducing synthesis and

release of mediators

including leukotrienes,

chemokines, and cytokines

from activated mast cells

Therapeutic approaches - Allergen immunotherapy

- The practice of administering gradually increasing quantities of

an allergen extract to an allergic subject to ameliorate the

symptoms associated with subsequent exposure to the causative allergen.

- Introduced in 1911

“The mechanisms of immunotherapy are complex....newer studies suggest that immunotherapy acts by modifying T-cell

responses either by immune deviation [shift from Th2 to Th1], T-cell anergy, or more likely both.” - WHO, 1998.

Risk: systemic anaphylaxis (potentially fatal)

- Holgate (1998) QJM 91:171

*

*

- In 1975, Godfrey (Clin. Allergy 5:201) investigated the occurrence of allergy and asthma in Gambian school children.

- Showed their association with urban dwelling, higher socioeconomic status and lower total circulating IgE levels.

- Suggested that in the rural setting, parasite infection was protective against the development of allergy and asthma.

- Holgate (1998)

QJM 91:171

Children in Caracas, Venezuela treated with antihelminthicdrugs - Lynch et al (1993) J. Allergy Clin. Immunol. 92:404.

Figure 12-91) Exposure to

infectious diseases

in early childhood

2) Environmental

pollution

3) Allergen levels

4) Dietary changes

Figure 12-8

Figure 12-11 Figure 12-12

Figure 12-13Eosinophils

• Eosinophils express FcεRI only after

activation

• On activation – release toxic granule

proteins and free radicals which can kill

microorganisms and parasites

• On activation – synthesis of chemical

mediators such as prostaglandins,

leukotrienes, and cytokines which amplify

the inflammatory response

Figure 12-14 Figure 12-19

Figure 12-20

Type II (antibody-dependent) hypersensitivity = IgG-mediated destruction of cells

Occur in any circumstance in which cells are exposed to high levels of cell-reactive IgG

antibody.

Destruction via:- complement-mediated lysis

- opsonization- ADCC

Examples include:

- transfusion reactions- Rh syndrome

Blood group antigens:

- Represent difference in terminal sugar residues on red cell glycoproteins

A = terminal N-acetylgalactosamine (NAcGal)

B = terminal galactose (Gal)O = no terminal residue

- Cross-react with antigens present on intestinal

microorganisms.

Type O individuals have antibodies to A and B groupsType A individuals have antibodies to the B antigen

Type B individuals have antibodies to the A antigenType AB individuals no antibodies

Type O = universal donor (cells cannot be destroyed byantibodies in recipients)

Type AB = universal recipient (have no antibodies that

could destroy transfused cells)

Figure 16-15

Rhesus (Rh) incompatibility

Drug-induced hemolytic anemia:

- Some drugs bind to erythrocyte proteins and create novel epitopes

- An individual may make an IgG response to the novel

epitopes

- The resulting IgG antibody may mediate complement-

mediated lysis of red cells - leading to hemolytic anemia

Treatment - cease using the drug

Type III hypersensitivity = immune complex-mediated hypersensitivity

- Binding of antibody to soluble antigen creates immune complexes.

- Immune complexes are normally removed from circulation (remember, C3b

binding to receptors on erythrocytes).

- High levels of immune complexes may result in adverse effects as a result of complement activation and localized inflammation.

Localized Type III reaction (Arthus reaction)

- Injection of antigen into the skin of an individual with high levels of antibody to the antigen (eg: insect bites [types I and III possible]).

- Intense localized inflammatory reaction characterized by influx of neutrophils.

1. Soluble Ag

2. Ag-Ab complex

3. Complement activation

4. Production of

complement

byproducts (C3a, etc)

5. Chemotaxis

6. Mast cell degranulation

7. Vascular endothelium

effects

Generalized Type III reactions:

- (sytemic lupus erythematosus, Rheumatoid arthritis)

- injection of antigen intravenously into an individual with high levels of antibody to the antigen.

- e.g. injection of horse antitoxins into an individualpreviously sensitized to horse immunoglobulin

-“serum sickness” - various symptoms including fever, rashes and sometimes glomerulonephritis asa result of immune complex deposition in thekidneys; vasculitis (deposition in arteries) orarthritis (deposition on synovial joints)

-Damage of tissue due to enzymes from “angry” cells

- Large quantities of soluble Ag-Ab complexes form in the blood and are not

completely removed by macrophages.

- These Ag-Ab complexes lodge in the capillaries between the endothelial cells

and the basement membrane.

- These Ag-Ab complexes activate the classical complement athway leading to

vasodilation and attraction of leukocytes to the area.

- The leukocytes discharge their killing agents and promote massive inflammation.

- This can lead to tissue death and hemorrhage.

• Type IV. Hypersensitivity Type IV

(delayed-type hypersensitivity, DTH)

– Macrophages

– Th1 T cells (DTH)

– Cytokines

– Examples: contact dermatitis

(formaldehyde, nickel, cosmetics, jewelry,

poison oak, poison ivy)

Figure 12-24

Figure 12-26 part 1 of 2 Figure 12-26 part 2 of 2

Cytokines:

-IFN-gamma

-MIF

-MCF

Contact Dermatitis

Figure 12-27 part 1 of 2 Figure 12-27 part 2 of 2

Figure 12-28 Figure 12-27 part 1 of 2

Figure 12-27 part 2 of 2

The End